KR930006190B1 - Preparation of 3-cyano-4-fluoro-phenol - Google Patents

Abstract

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Description

[Name of invention]

Preparation of 4-fluorophenol

Detailed description of the invention

The present invention relates to the preparation of 4-fluorophenol. Fluorophenols are important compounds because, in some cases, they are intermediates to the synthesis of compounds with pharmacological or pesticidal activity, which are the fluoro-logues of natural products.

Fluorophenols are usually prepared by one of two routes.

(Iii) from chloronitrobenzene via halogen exchange, reduction, diazotization and hydrolysis,

(Ii) By hydrolysis from bromo fluorobenzene, since the range of chloronitrobenzene undergoing halogen exchange reactions is limited, only a few fluorophenols can be produced at a considerable cost by route. . The starting material (substituted) -bromofluorobenzene used in the second route is not readily available. Another method is mentioned in German Patent Publication No. 1213848, wherein 4,4-difluoro-3,5-dimethoxycyclo hexadienone is reduced by using zinc powder and acetic acid to produce 4-fluoro. The preparation of -3,5-dimethoxyphenyl is introduced in detail. Although the use of explosive fluoroperchlorates in the preparation of starting materials for 3,5-dimethoxyphenol is a matter of concern, the process generally involves starting with at least one of the two positions which are meta to the keto group being substituted by a lower alkyl- or alkoxy group. It is limited to material. Other reducing conditions known to be suitable besides using zinc and acetic acid are chromium acetate (II), chromium chloride (II) or a mixture of sodium iodide and acetic acid.

According to the present invention, the fluorohalocyclohexadienone of Structural Formula (II) is represented by Structural Formula AZ (where Z is as defined below, A represents hydrogen or an alkali metal atom, provided that both A and Z represent hydrogen). Wherein the reaction is carried out in the presence of an additional Group VIII metal hydrogenation catalyst). A process for the preparation of 4-fluorophenol of formula (I) is provided.

Wherein n is 0-3, each R independently represents a halogen atom or an alkyl, alkoxy, cyano or optionally substituted amino group, Z represents a hydrogen or halogen atom or a cyano group, and X represents a halogen atom Indicates.

3-cyano-4-fluorophenol of formula (I) (i.e. compound of formula (I) wherein Z is cyano group), in particular 3-cyano-4-fluorophenol, is novel and One aspect of the invention is constituted.

These compounds are extremely homeostatic starting materials for the production of more complex molecules because 3-cyano-groups can be readily derived by known methods.

Substituents R each is an alkyl or alkoxy group such as C _1-5 alkyl or alkoxy group, especially methyl or methoxy, preferably containing up to 4 carbon atoms: or a cyano or optionally substituted amino group such as amino, C _{1 -5} alkylamino or di (Ci- ₅ ) amino group, or halogen atom, preferably chlorine or fluorine atom. R is preferably chlorine or methyl. n is preferably 0 or 1, preferably 0.

Another reactant compound of formula A-Z may be hydrogen gas, hydrogen halide, hydrogen cyanide or alkali metal hydride, halide or cyanide, depending on the choice of A and Z. In one particular embodiment A is an alkali metal atom and Z is a fluorine atom or preferably a cyano group. In another particular embodiment both A and Z are hydrogen, followed by the Group VIII metal hydrogenation catalyst which is platinum on a carbon support. Other catalysts suitable for the present invention include, for example, metallic or activated or supported palladium or nickel catalysts.

The reaction can be carried out by conveniently mixing the reactants in an inert solvent followed by the addition of a catalyst and the addition and mixing may be in any order, if necessary. The reaction can be conveniently carried out at 0-150 ° C., preferably 0-75 ° C. It is very convenient to carry out at ambient temperature (eg 20-25 ° C.). A reaction time of 5 minutes-1 hour was found to show good results.

In the compound of formula II, the halogen atom represented by X may be a fluorine, chlorine, bromine or iodine atom, but X generally represents a fluorine atom since a difluoro compound can be obtained more economically. . A particularly convenient method for preparing 4-fluoro-4-halocyclohexadienone is mentioned in British Patent Application No. 8501917.

When using this method it is possible to carry out two successive reactions without separating the intermediate fluorohalocyclo hexadienone.

According to a preferred method of the present invention, the fluorohalocyclohexadienone of formula (II) is reacted with hydrogen fluoride and Pb (IV) compounds in the presence of a compound that acts as a base for HF Is generated.

Wherein Q represents a hydrogen atom or an alkyl, acyl or aryloxycarbonyl group, X 'represents hydrogen or X and X, n and R are as defined above.

Group -OQ is -OH group (compound of formula (I) is phenol), alkoxy group (compound of formula (III) is phenol), alkoxy group (compound of formula (I) is phenol ether), acyl It may be a time period (phenol ester) or an aryloxycarbonyloxy group (phenylaryl carbonate).

It is preferable that the aryl component of an aryloxy group is a phenyl group. Substituent Q is preferably hydrogen, acetyl or phenoxycarbonyl group.

Such as Pb (Ⅳ) compounds _{PbF 4, PbCl 4, Pb (} CO 3) 2 or Pb (OAc) _4, such as Pb (Ⅳ) salts or PbO ₂ simple Pb (Ⅳ) acid hwanmul same or Pb ₃ O ₄ Pb ( IV) oxides or salts containing the compounds or mixtures thereof.

The Pb (IV) compound may conveniently be lead oxide, carboxyTLFlate, carbonate or fluoride. Preferred Pb (IV) compounds are PbO ₂ , Pb (OAc) ₄ , PbF ₂ (OAc) ₂ and in particular PbF ₄ . Ac used herein represents the acetyl group CH ₃ .CO.

If no Pb (IV) compound is present but replaced by a simple compound such as MnO ₂ , Mn (OAc) ₃ or H ₂ O ₂ , no fluorination occurs. Although the exact mechanism of the reaction of the present invention is not known, it is clear that the Pb (IV) compound does not only act as an oxidant.

It has been found that at least 1 mole of Pb (IV) compound per mole of structural formula (III), and at least 2 moles per mole of X when hydrogen is a hydrogen atom, are very effective.

Compounds which act as bases on HF, i.e., receive protons from HF, or give electrons to HF, are conveniently fluoride salts: nitrogen compounds of the formula NR ¹ R ² R ³ , wherein R ¹ , R ² and R ₃ Each independently represent hydrogen or alkyl, or R ¹ and R ² together form an alkylene group or R ¹ , R ² and R ³ together form an alkylidene group); Metal hydroxides or alkali metal fluorides, in particular KF. PbF ₄ which has a dual function as a Pb (IV) compound and as a compound which acts as a base for HF can also be used. The nitrogen compound may for example be diethylamine, triethylamine, piperidine, pyridine or pyrazine. This is preferably pyridine because the pyridine / HF system is convenient for use in the laboratory or in the industry (low steam pressure). The metal hydroxide may optionally be an alkali metal hydroxide in aqueous solution.

The appropriate amount of HF and base should be at least sufficient to provide enough fluorine atoms as necessary for the reaction with the phenolic compound. Using an excess is convenient because this increases the conversion of (more expensive) phenolic compounds.

It is not necessary to add solvents or diluents or to operate in a multiphase system. However, if the phenol has a solubility of more than slightly dissolved in the HF / base system, the reaction is a liquid diluent such as liquid aliphatic, optionally halogenated, hydrocarbon, ether, or its incompatible with hydrogen fluoride or substantially inert to hydrogen fluoride. It is preferably carried out in the presence of a mixture, advantageously in the presence of dichloromethane or n-pentane.

The reaction of the compound of formula III may be conveniently carried out at -30-100 ° C, preferably 0-60 ° C. The reaction is conveniently carried out at ambient temperature such as 20 ° C.

The final product of formula (I) may in some cases be used as an intermediate in the pharmaceutical or pesticide chemical industry in preparing compounds that are fluoro homologues of natural chemicals.

[Examples]

All yields are based on cyclohexadienone usage unless stated otherwise and are given in mole percent. Yield was measured by gas / liquid chromatography.

Example 1

Preparation of 4-Fluolphenol from 4,4-difluorocyclohexadienone

a) 400 mg of 4,4-difluorocyclohexadienone and 40 mg of catalyst (10% platinum on carbon) in 25 ml of methanol were stirred under a hydrogen atmosphere for 10 minutes under 25 ° C atmospheric pressure.

-플루오로페놀이 90% 이상의 수율로 생성되었다.

-Fluorophenols were produced in yields of 90% or higher.

b) The experiment was repeated using Raney-nickel as catalyst. After 60 minutes at 60 ° C. and 35 atmospheres, the yield of p -fluorophenol was 65%.

Example 2

Preparation of 3-cyano-4-fluolphenol from 4,4-difluorocyclohexadienone

4m moles of potassium cyanide and 4,4-difluorocyclohexadiene in 0.5 ml of diethylformamide formed 90% yield of 3-cyano-4-fluorophenol when 2m moles were mixed at room temperature for 10 minutes. It became. The spectral data of this novel compound are as follows:

Mass spectrum: m / e 137 (M ⁺ ); 109 (M-CO, H), 82, 57.

¹ H magnetic resonance spectra: (D ₇ -DMF): δ4.43 (s, 1H), 6.09 (m, 1H), 7.03 (m, 1H), 7.15 (m, 1H).

13C magnetic resonance spectrum: (d ⁷ -DMF): δ` 157.2, 155.8, 123.4, 119.2, 117.6, 114.8, 100.7.

Example 3

Preparation of 4-fluorophenol from 4-chloro-4-fluorocyclohexadienone prepared from 4-chlorophenol without intermediate separation

-클로로페놀 20m몰을 60분에 걸쳐 PbO₂20ml몰, 피리딘중 70% w/wHF 10ml 및 CH₂Cl₂50ml로 구성된 교반된 혼합물에 25℃에서 첨가했다. 이어 반응혼합물을 60분간 더 교반했다. 이어 HF-상으로부터 유기층을 경사분리하고 동일용량의 물로 추출했다. 용매를 증류하고 잔사에 메탄올 10ml와 촉매(탄소상 10% w/w Pt)의 40mg을 첨가했다. 이 혼합물을 25℃, 대기압에서 수소분위기하에서 30분간 교반했다. GLC분석결과

-클로로페놀 사용량을 기준으로

-플루오로페놀이 20% 수율로 얻어졌다.In 20 ml of CH ₂ Cl ₂

20 mmol of chlorophenol were added at 25 ° C. to a stirred mixture consisting of 20 ml mol of PbO ₂ , 10 ml 70% w / wHF in pyridine and 50 ml CH ₂ Cl ₂ over 60 minutes. Then, the reaction mixture was further stirred for 60 minutes. The organic layer was then decanted from HF-phase and extracted with water of equal capacity. The solvent was distilled off and 10 ml of methanol and 40 mg of catalyst (10% w / w Pt on carbon) were added to the residue. The mixture was stirred at 25 ° C. under atmospheric pressure for 30 minutes under hydrogen atmosphere. GLC analysis result

Based on chlorophenol usage

-Fluorophenol was obtained in 20% yield.

Claims (7)

A process for producing 4-fluorophenol of formula (I), characterized by reacting fluorohalocyclo hexadienone of formula (II) with a compound of formula A-Z.

Wherein n is 0-3, R each independently represents a halogen atom, Z represents a hydrogen atom or a cyano group, X represents a halogen atom, A represents a hydrogen or an alkali metal atom, and A When both and Z represent hydrogen, the reaction is carried out in the presence of an additional Group VIII metalhydrogenation catalyst. The method of claim 1 wherein n is zero. The process according to claim 1 or 2, wherein when both A and Z are hydrogen, the Group VIII metalhydrogenation catalyst is platinum on a carbon support. The method according to claim 1 or 2, wherein A is an alkali metal atom and Z is a cyano group. The method according to claim 1 or 2, wherein Z is a CN group. The process according to claim 1 or 2, wherein the reaction is carried out at a temperature of 0 ° -75 ° C. The fluorohalocyclo of formula (II) according to claim 1 or 2, wherein the compound of formula (III) is reacted with hydrogen fluoride and a Pb (IV) compound in the presence of a compound which acts as a base for HF. Method of producing hexadienone.

Wherein Q represents hydrogen, alkyl, acyl or aryloxy carbonyl, X 'is hydrogen or X and n and R are as defined in claim 1.